Unaffected Women Research Articles

A novel loss-of-function heterozygous BRCA2 c.8946_8947delAG mutation found in a Chinese woman with family history of breast cancer.

Breast cancer is the most frequent female malignancy worldwide. Among them, some cases have hereditary susceptibility in two leading genes, BRCA1 and BRCA2. Heterozygous germ line mutations in them are related with increased risk of breast, ovarian and other cancer, following autosomal dominant inheritance mode. For purpose of early finding, early diagnosis and early treatment, mutation detecting of BRCA1/2 genes was performed in unselected 300 breast or ovarian patients and unaffected women using next-generation sequencing and then confirmed by Sanger sequencing. A non-previously reported heterozygous mutation c.8946_8947delAG (p.D2983FfsX34) of BRCA2 gene was identified in an unaffected Chinese woman with family history of breast cancer (her breast cancer mother, also carrying this mutation). The BRCA2-truncated protein resulted from the frame shift mutation was found to lose two putative nuclear localization signals and a Rad51-binding motif in the extreme C-terminal region by bioinformatic prediction. And then in vitro experiments showed that nearly all the mutant protein was unable to translocate to the nucleus to perform DNA repair activity. This novel mutant BRCA2 protein is dysfunction. We classify the mutation into disease causing and conclude that it is the risk factor for breast cancer in this family. So, conducting the same mutation test and providing genetic counseling for this family is practically meaningful and significant. Meanwhile, the identification of this new mutation enriches the Breast Cancer Information Core database, especially in China.

Maternofetal outcome of asymptomatic bacteriuria among pregnant women in a Nigerian Teaching Hospital.

IntroductionAsymptomatic bacteriuria has been reported to be associated with adverse pregnancy outcome. This study sought to determine the prevalence and complications of asymptomatic bacteriuria amongst parturient in the University of Port Harcourt Teaching Hospital (UPTH).MethodsThe study was a prospective cohort study involving 220 eligible antenatal attendees. Urine culture and sensitivity was conducted for each participant and the fetomaternal outcome between affected and unaffected women were compared and p value <0.05 was considered significant.ResultsSixty-five of the participants had asymptomatic bacteriuria giving a prevalence of 29.5%. Twenty-three (35.4%) cultures yielded Klebsiella spp while Fifty-eight (89%) of the cultured organisms were sensitive to Nitrofurantoin. There was no statistical difference in the rate of prelabour rupture of membranes, preeclampsia, preterm delivery, birth asphyxia and low birth weight between affected and unaffected women.ConclusionContrary to widely held view, there was no significant increase in adverse pregnancy outcome amongst affected women.

Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation

Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation

Prevalence of asymptomatic heart failure in formerly pre-eclamptic women: a cohort study.

After pre-eclampsia (PE), the prevalence of structural heart disease without symptoms, i.e. heart failure Stage B (HF-B), may be as high as one in four women in the first year postpartum. We hypothesize that a significant number of formerly pre-eclamptic women with HF-B postpartum are still in their resolving period and will not have HF-B during follow-up. In this prospective longitudinal cohort study, we included 69 formerly pre-eclamptic women who underwent serial echocardiographic measurements at 1 and 4 years postpartum. HF-B was diagnosed as left ventricular hypertrophy (left ventricular mass index (LVMi) > 95 g/m2 ), concentric remodeling (relative wall thickness > 0.42 and LVMi ≤ 95 g/m2 ), mild systolic dysfunction (left ventricular ejection fraction > 40% and < 55%) or asymptomatic valvular disease. Women were subdivided and analyzed according to HF-B outcome: no HF-B at either visit; HF-B at first visit only; HF-B at second visit only; HF-B at both visits. The prevalence of HF-B in formerly pre-eclamptic women was 23% in the first year postpartum and 23% after 4 years. At the second visit, HF-B had resolved in 62.5% of affected women but was newly developed in 19% of initially unaffected women. At the first visit, 56% of women diagnosed with HF-B had reduced systolic function whereas at the second visit 69% of women with HF-B had concentric remodeling with mostly normal ejection fraction, consistent with diastolic dysfunction. The prevalence of HF-B can be considered consistently high (1 in 4) amongst formerly pre-eclamptic women at follow-up. Nonetheless, at an individual level, more than 60% of women found initially to be affected by HF-B will recover, whilst about 20% of formerly pre-eclamptic women with normal echocardiography in the first year postpartum will develop HF-B over the following years. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of Preeclampsia in Early Pregnancy by Estimating the Spot Urinary Albumin/Creatinine Ratio.

To assess whether a spot urinary albumin:creatinine ratio (ACR) measured before 20weeks of gestation can predict subsequent development of preeclampsia. The ACR was determined from midstream urine sample taken between 17 and 20weeks of gestation. Urine albumin was measured by immunoturbidimetric method using commercially available kit (Beckman Coulter) through Beckman AU 480 fully automated biochemistry analyzer. Urine creatinine was measured by modified kinetic Jaffe reaction without deproteinization.[Formula: see text]Participants were then followed until delivery. Primary outcome measure was preeclampsia, secondary outcome measures were gestational hypertension, gestational diabetes mellitus, IUGR, and normal range estimate of urinary albumin-to-creatinine ratio was established. The median spot urinary albumin-to-creatinine ratio measured between 17 and 20weeks of gestation was 5.2mg/g of creatinine (2.5-9.6). Women who subsequently developed preeclampsia had higher spot urinary albumin-to-creatinine ratio (median 30.795 [9.7-92.8]) in comparison with women who developed gestational hypertension (median 5.2 [0.7-7.2]) and unaffected women (median 5.2 [2.5-9.6]). The urinary albumin-to-creatinine ratio of the mother who developed IUGR was significantly higher. By ROC analysis, the optimum ACR to predict preeclampsia was 9.85mg/g of creatinine. The relative risk of developing preeclampsia in women with urinary albumin-to-creatinine ratio more than 9.85mg/g of creatinine was higher than in the women who had urinary albumin-to-creatinine ratio less than 9.85mg/g of creatinine. A spot urinary albumin-to-creatinine ratio of more than 9.8mg/g of creatinine can predict the development of preeclampsia in later pregnancy with the sensitivity and specificity of 67 and 76%, respectively. However, additional studies and cost-benefit analysis are required to confirm these finding before recommending this test for screening purposes.

BRCA1 and BRCA2 germline mutations in Asian and European populations

Women who carry a pathogenic mutation in the breast cancer susceptibility genes BRCA1 or BRCA2 ( BRCA ) have markedly increased risks of developing breast and ovarian cancers during their lifetime. It has been estimated that their breast and ovarian cancer risks are in the range of 46-87% and 15-68%, respectively. Therefore it is of utmost clinical importance to identify BRCA mutation carriers in order to target unaffected women for prevention and/or close surveillance and to help affected women choose the best chemotherapy regimen. Genetic testing for BRCA germline mutations is expanding in clinical oncology centers worldwide. Given the high costs of complete BRCA gene screens, a lot of effort has been expended on deciding upon whom to test. Relevant issues involved in decision making include the prior probability of a woman having a BRCA mutation, which is a function of her age and her disease status, her ethnic group, and her family history of breast or ovarian cancer. The frequency and spectrum of mutations in these genes show considerable variation by ethnic groups and by geographic regions. Most studies have been conducted in European and North American populations, while studies in Asian, Hispanic, and African populations are fewer. In most populations, many BRCA mutations were identified, which were distributed all over the genes. However, in some populations, a relatively small number of specific BRCA mutations are recurrent and account for the majority of all mutations in that population. Many of the recurrent mutations are founder mutations, which were derived from a common ancestor. Founder mutations are present in Ashkenazi Jewish, European, and Islander (Faroe, Easter, and Pitcairn) populations. Such mutations have also been identified in patients from several Asian, South American, and African countries. Population-specific genetic risk assessment and genetic mutation screening have been facilitated at low costs. Given that mutations in the BRCA genes are distributed in populations throughout the world, it is important that the benefits of genetic testing and of targeted therapies be made available not only to women from developed countries in Europe and North America, but also to those from less developed countries in Asia, Africa and South America.

Higher autism in children of women with psychiatric diagnoses

BackgroundTo determine the extent to which medical record history of maternal psychiatric diagnoses was associated with offspring autism risk in a large, socio-demographically diverse birth cohort. MethodThis retrospective cohort study linked hospital discharge records for 8,951,763 California singleton births occurring 1/1/91-12/31/08 from the Office of Statewide Health Planning and Development with diagnostic and service records from the Department of Developmental Services. Medical records documenting maternal mood and anxiety disorders and schizophrenia ICD-9-CM codes were identified, and 42,423 children were categorized with a DSM-IV diagnosis of ‘autistic disorder’. Log-linear Poisson models explored the relationships between maternal psychiatric disorders and autism, adjusting for maternal education, race, country of birth, and parental age. ResultsRates of maternal psychiatric diagnoses were lower than expected for the population, reflecting under-recognition and under-reporting by inpatient clinicians. In adjusted analyses, mothers diagnosed with one individual psychiatric condition were 1.2–2.8 times more likely to have a child who developed autism. Mothers diagnosed with any one or more psychiatric condition were twice as likely to have a child with autism compared with unaffected or unreported women (RR=1.97; 95% CI 1.83–2.12). ConclusionsWomen with a documented inpatient medical record history of psychiatric diagnosis were nearly twice as likely as women without such diagnoses to have a child later diagnosed with autism. These findings highlight the need for routine prenatal screening for psychiatric conditions, as well as enhanced neurobehavioral assessment of children born to these mothers to detect early autism signs and optimize intervention timeliness.

Risk algorithms that include pathology adjustment for HER2 amplification need to make further downward adjustments in likelihood scores

To assess the need for adjustment in the likelihood of germline BRCA1/2 mutations in women with HER2+ breast cancers. We analysed primary mutation screens on women with breast cancer with unequivocal HER2 overexpression and assessed the likelihood of BRCA1/BRCA2 mutations by age, oestrogen receptor status and Manchester score. Of 1111 primary BRCA screens with confirmed HER2 status only 4/161 (2.5%) of women with HER2 amplification had a BRCA1 mutation identified and 5/161 (3.1%) a BRCA2 mutation. The pathology adjusted Manchester score between 10 and 19% and 20%+ thresholds resulted in a detection rate of only 6.5 and 15% respectively. BOADICEA examples appeared to make even less downward adjustment. There is a very low detection rate of BRCA1 and BRCA2 mutations in women with HER2 amplified breast cancers. The Manchester score and BOADICEA do not make sufficient downward adjustment for HER2 amplification. For unaffected women, assessment of breast cancer risk and BRCA1/2 probability should take into account the pathology of the most relevant close relative. Unaffected women undergoing mutation testing for BRCA1/2 should be advised that there is limited reassurance from a negative test result if their close relative had a HER2+ breast cancer.

Endometriosis and pregnancy complications: a Danish cohort study

To study the association between endometriosis and risk of pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and small for gestational age (SGA), in a large Danish birth cohort, while taking fertility treatment into account. Population-based study. Not applicable. A total population of 82,793 singleton pregnancies from the Aarhus Birth Cohort (1989 through 2013); 1,213 women had a diagnosis of endometriosis, affecting 1,719 pregnancies. None. Pre-eclampsia, cesarean section, postpartum hemorrhage, preterm birth, and SGA. Endometriosis was associated with an increased risk of preterm birth (adjusted odds ratio [AOR] 1.67, 95% confidence interval [CI] 1.37-2.05), with the risk being highest for very preterm birth (AOR 1.91, 95% CI 1.16-3.15). Compared with unaffected women, women with endometriosis also had an increased risk of pre-eclampsia (AOR 1.37, 95% CI 1.06-1.77) and cesarean section (AOR 1.83, 95% CI 1.60-2.09). Assisted reproductive technology did not explain these findings. No association was found between endometriosis and postpartum hemorrhage or SGA. Women with endometriosis were at increased risk of pre-eclampsia, preterm birth, and cesarean section, irrespective of use of assisted reproductive technology.

Association between circulatory levels of adipokines and bone mineral density in postmenopausal women.

Epidemiological evidence indicates that excess fat may be beneficial for bone health, offering protective effects against the onset of postmenopausal osteoporosis. Experimental data suggest that this link might be due to the direct effect of adipokines on bone tissue. Confirmatory evidence of this association, however, remains limited. The levels of a panel of selected adipokines including interleukin (IL)-6, -8, -1β, adipsin, lipocalin-2/neutrophil gelatinase-associated ipocalin, tumor necrosis factor alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, hepatocyte growth factor, resistin, leptin, and adiponectin in a group of osteopenic and osteoporotic postmenopausal women were compared with those of unaffected women (n = 127). Univariate analysis revealed that leptin and adiponectin were significantly correlated with bone mineral density (BMD). In particular, leptin was positively associated with BMD of the spine (r = 0.22, P < 0.05), femoral neck (r = 0.23, P < 0.05), trochanter (r = 0.20, P < 0.05), and total hip (r = 0.27, P < 0.01), whereas adiponectin was inversely correlated with BMD at the trochanter (r = -0.21, P < 0.05). No correlations were, however, significant after adjusting for body fat variables. Stratification of the sample according to IL-6 levels revealed that adiponectin remained significantly inversely associated with BMD, regardless of fat levels and age (β=-0.29, P < 0.05; r = 0.198) in the subgroup of participants with low levels of IL-6. Our data suggest that circulating adiponectin is inversely associated with markers of bone health in postmenopausal women, and that the interaction is influenced by IL-6 levels.

Association of PALB2 sequence variants with the risk of early-onset breast cancer in patients from Turkey.

The PALB2 gene, has been accepted as a moderate-penetrance gene associated with breast cancer susceptibility and this gene product is involved in the DNA damage repair pathway via co-localization with BRCA2. Germline PALB2 mutations are associated with an increased breast cancer risk. However, the prevalence of the diverse types of PALB2 variants depend on the population. Thus, the aim of the present study was to determine, for the first time, the prevalence of PALB2 variants in a Turkish population of BRCA1/BRCA2-negative early-onset patients with breast cancer. In total, 223 Turkish patients with BRCA1/BRCA2 negative early-onset breast cancer and 60 unaffected women were included in the study. All the coding exons and intron/exon boundaries of PALB2 were subjected to mutational analysis by heteroduplex analysis (HDA)and DNA sequencing. Eighteen PALB2 variants were found in breast cancer patients within the Turkish population. Three variants (c.271G>A, c.404C>A and c.2981T>A) have not been previously reported. In addition, nine intronic variants were described, and this study is the first to describe the c.1685-44T>A intronic variant. The prevalence of possible pathogenic PALB2 variants was found to be 4.03% in BRCA1/2-negative Turkish patients with early-onset breast cancer. Different variants of PALB2 have been reported in the literature, and the prevalence of these variants could different for each population. This is the first study to investigate the prevalence of PALB2 variants in Turkish patients with early-onset breast cancer.

Beyond the Bedroom: Cognitive, Affective, and Behavioral Responses to Partner Touch in Women With and Without Sexual Problems

Women with female sexual problems (FSP) are more likely than unaffected women to demonstrate negative appraisals, negative affect, and avoidance of sexual activity. Research suggests affected women also experience negative affect and avoidance in response to intimate partner contact for fear it will lead to sex. This online study examined whether women with FSP (N = 157) and without FSP (N = 129) exhibited different perceptions, affective reactions, and behavioral responses to hypothetical touch occurring outside sexual activity. Women (Mage = 30.70; SD = 6.66) were randomly assigned to one of three conditions representing hypothetical interactions with their partner (affectionate, sexual, or no touch), and answered questions about their perceptions of their partner’s sexual intentions and their own anticipated negative affect and behavioral avoidance. Women with FSP reported higher perceptions of sexual intent, negative affect, and avoidance in the sexual touch condition, and higher negative affect in the affectionate touch condition, than women without FSP. Results highlight that women with FSP have more negative reactions to partners’ hypothetical affectionate and sexual touch than women without FSP. Interventions for FSP may benefit from targeting women’s perceptions, affective reactions, and behavioral reactions to partner touch when it occurs outside of explicitly sexual contexts.

Incontinence Medication Response Relates to the Female Urinary Microbiota

Many adult women have resident urinary bacteria (urinary microbiome/microbiota). In adult women affected by urinary urgency incontinence (UUI), the etiologic and/or therapeutic role of the urinary microbiome/microbiota remains unknown. We hypothesized that microbiome/microbiota characteristics would relate to clinically relevant treatment response to UUI medication per os. Adult women initiating medication treatment orally for UUI and a comparator group of unaffected women were recruited in a tertiary care health-care system. All participants provided baseline clinical data and urine samples. Women with UUI were given 5 mg solifenacin, with potential dose escalation to 10 mg for inadequate UUI symptom control at 4 weeks. Additional data and urine samples were collected from women with UUI at 4 and 12 weeks. The samples were assessed using 16S ribosomal RNA (rRNA) gene sequencing and enhanced quantitative urine culturing. The primary outcome was treatment response as measured by the validated Patient Global Symptom Control (PGSC) questionnaire. Clinically relevant UUI symptom control was defined as a 4 or 5 score on the PGSC. Diversity and composition of the urinary microbiome/microbiota of women with and without UUI differed at baseline. Women with UUI had more bacteria and a more diverse microbiome/microbiota. The clinical response to solifenacin in UUI participants was related to baseline microbiome/microbiota, with responders more likely to have fewer bacteria and a less diverse community at baseline. Nonresponders had a more diverse community that often included bacteria not typically found in responders. Knowledge of an individual’s urinary microbiome/microbiota may help refine UUI treatment. Complementary tools, DNA sequencing, and expanded urine culture provide information about bacteria that appear to be related to UUI incontinence status and treatment response in this population of adult women.

Analysis of pre- and post-pregnancy issues in women with hyperemesis gravidarum.

The purpose of this study is to determine the frequency of reporting of both pre-pregnancy and post-pregnancy psychosocial and physical issues in women with hyperemesis gravidarum (HG). Conditions in 449 women with HG were compared to 459 unaffected women (controls). Binary responses were analyzed using either Chi-squared or Fishers Exact test. Continuous responses were analyzed using a t-test. Among 60 pre-pregnancy conditions surveyed, 10 common (>5%) maternal pre-pregnancy conditions were significantly more frequently reported by women with HG. Twenty rare (<5% controls) pre-pregnancy conditions with significantly increased reporting in the HG group were identified. Thirty (50%) pre-pregnancy conditions were similarly reported between cases and controls. Among 80 post-pregnancy factors surveyed, women with HG also showed significantly higher reporting for 7 common and 50 rare post-pregnancy outcomes. Women with HG are significantly more likely to self-report physical and psychosocial issues both before and after pregnancy.

Abstract 796: ERCC3 R109X is a moderate risk breast cancer risk variant in Ashkenazi Jews

Abstract Background: Known gene mutations account for approximately 50% of the risk for breast cancer. However, a considerable fraction of heritable risk remains unexplained. Fifteen percent of the risk is accounted for by BRCA1/2 and another 3% by TP53, PTEN, LKB1 and CDH1. CHEK2, ATM, PALB2, BRIP1, RAD51C, RAD51D and BARD1 account for 4%, while SNPs discovered from large multicenter genome-wide association studies explain another 14% of the heritable risk. Founder mutations in the DNA repair pathway genes such as BRCA1 and BRCA2 account for the majority of AJ breast cancer mutations. Methods: We performed exome sequencing of 49 early onset (age &amp;lt;35) breast cancer cases, and 85 BRCA wild type familial breast cancer cases, all of Ashkenazi Jewish (AJ) from the New York City area. A recurrent truncating mutation was then analyzed in 3131 breast cancer cases and 2716 unaffected women of Ashkenazi ancestry from New York and Israel. Using CRISPR and overexpression systems on the human mammary epithelial cell line HMLE, transcript and protein levels were assayed for the mutant and compared to wild-type. Treatment with IlludinS and UVC were performed to assess DNA damage response. Finally, clonogenic survival assay was also performed. Results: Amongst the DNA repair pathway genes, exome sequencing revealed a heterozygous recurrent truncating mutation in ERCC3 (R109X) in 2 of 49 early onset breast cancer cases of AJ ancestry and 4 familial AJ probands. Taqman genotyping in a case control setting from New York and Israel revealed 54 mutation carriers in 3131 cases and 32 in the 2716 controls. In total, there were 60 heterozygotes detected in 3209 cases and 32 in 2716 controls [OR 1.59 (95% CI 1.01-2.50)]; p = 0.02 Fisher one- tailed). Functional studies using CRISPR and overexpression systems on human mammary epithelial cells, show that the mutation results in lower transcript levels and this reduction is effected by nonsense mediated decay of the mutant transcript. Western blotting showed that the mutation resulted in a smaller protein (∼12kDa). Clonogenic assays showed similar survival rate of mutant and wildtype under UVC exposure, however the mutant cell line showed significantly smaller colony size demonstrating a growth disadvantage that was further increased upon DNA damage. Treatment with fungal sesquiterpene IlludinS, a known sensitizer to mutant ERCC3 cell lines, showed drastically reduced survival when compared to the wild type human mammary epithelial cells. Conclusions: We demonstrate that ERCC3 is a moderate risk gene for breast cancer in individuals of Ashkenazi ancestry. ERCC3 is somatically mutated in multiple cancers including breast, ovarian and pancreatic cancers, however its role as a cancer susceptibility gene requires further elucidation. Additional functional and population genetic studies to further characterize this novel ERCC3 variant are underway. Citation Format: Joseph Vijai, Sabine Topka, Kara Maxwell, Vignesh Ravichandran, Tinu Thomas, Danylo Villano, Ann Maria, Pragna Gaddam, Anne Lincoln, Steven Hart, Susan Neuhausen, Mark Robson, Jeffrey Weitzel, Mark Daly, Katherine Nathanson, Fergus Couch, Gadi Rennert, Kenneth Offit. ERCC3 R109X is a moderate risk breast cancer risk variant in Ashkenazi Jews. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 796.

Women's Reproductive History Before the Diagnosis of Incident Endometriosis.

Endometriosis is a gynecologic disease reported to be associated with infertility and, possibly, adverse pregnancy outcomes. While considerable research focuses on pregnancy outcomes following diagnosis and/or treatment, few data actually describe women's reproductive history before diagnosis for a more complete understanding of endometriosis and reproduction. The study sample comprised 473 women (aged 18-44 years) undergoing laparoscopies or laparotomies, irrespective of surgical indication at 14 clinical sites, during the period 2007-2009. Upon enrollment and before surgery, women were queried about pregnancy intentions and the time required to become pregnant for planned pregnancies. Endometriosis was defined as surgically visualized disease. Using discrete time survival analysis, we estimated fecundability odds ratios (FORs) and 95% confidence intervals (CIs) to assess time to pregnancy (TTP) after adjusting for potential confounders (age, body composition, cigarette smoking, site). Generalized estimating equations accounted for multiple pregnancy attempts per woman. FORs <1.0 denote a longer TTP or diminished fecundity. Approximately 66% and 69% of women with and without endometriosis, respectively, reported having a planned pregnancy before surgery, respectively. After adjustment, an endometriosis diagnosis was associated with ≈29% reduction in fecundity or a longer TTP across all pregnancy-trying attempts (adjusted FOR = 0.71; 95% CI 0.46-1.10). While FORs were consistently <1.0, irrespective of endometriosis staging, CIs included 1. Women with endometriosis had a longer TTP than unaffected women, irrespective of disease severity, although the findings did not achieve significance. Prior reproductive history may be informative for predicting fecundity and pregnancy outcomes following diagnosis/treatment.

Adherence to Recommended Risk Management among Unaffected Women with a BRCA Mutation.

Identifying unaffected women with a BRCA mutation can have a significant individual and population health impact on morbidity and mortality if these women adhere to guidelines for managing cancer risk. But, little is known about whether such women are adherent to current guidelines. We conducted telephone surveys of 97 unaffected BRCA mutation carriers who had genetic counseling at least one year prior to the survey to assess adherence to current guidelines, factors associated with adherence, and common reasons for performing and not performing recommended risk management. More than half of participants reported being adherent with current risk management recommendations for breast cancer (69%, n=67), ovarian cancer (82%, n=74) and both cancers (66%, n=64). Older age (OR=10.53, p=0.001), white race (OR=8.93, p=0.019), higher breast cancer genetics knowledge (OR=1.67, p=0.030), higher cancer-specific distress (OR=1.07, p=0.002) and higher physical functioning (OR=1.09, p=0.009) were significantly associated with adherence to recommended risk management for both cancers. Responses to open-ended questions about reasons for performing and not performing risk management behaviors indicated that participants recognized the clinical utility of these behaviors. Younger individuals and those with lower physical functioning may require targeted interventions to improve adherence, perhaps in the setting of long-term follow-up at a multi-disciplinary hereditary cancer clinic.

Increased Reach of Genetic Cancer Risk Assessment as a Tool for Precision Management of Hereditary Breast Cancer.

Genetic cancer risk assessment (GCRA) is an interdisciplinary clinical practice that incorporates genetics, oncology, and counseling skills to quantify risk and implementmore precise care for individualswith inheritedcancerpredisposition.1GCRA is warranted for individuals with features suggesting hereditary cancer, such as early age at onset, triple-negative breast cancer, and/or a family history of breast or ovarian cancer. The cloning of theBRCA1 gene on chromosome 17 in 1994, and of a second high-risk locus (BRCA2) on chromosome 13 in 1995, ushered in an erawith increasing appreciation of the potential for oncogenetics to influence breast cancer screening, treatment, andprevention.Thesubsequentdecadeshavebeen marked by an ever greater understanding of gene-specific pathology and age-specific risk for BRCA-associated breast cancers, as well as a growing understanding of hormonal and genetic modifiers of risk.1 Commercial testing for BRCA1 and BRCA2 became available in theUnitedStates in1996,andprofessional societypolicy statements and practice guidelines affirm the value of BRCA testing for identifyingandmanaginghigh-risk individuals and families.2,3 In this issue, Rosenberg and colleagues4 describe BRCA gene testing and surgical decision-making outcomes amongparticipants in theYoungWomen’sBreastCancerStudy (YWS), amulticentercohortofwomen40yearsoryoungerwho had limited-stage breast cancer (ie, stage 0-II) and received GCRA at academic and community clinics between 2006 and 2014.Participantsweremostlywhite,well educated (85%completed college and/or graduate school), and virtually all had health insurance. One positive finding of the study was a relatively robust reach, in that most of the YWS study participants (87%) received BRCA gene testing within 1 year of their breast cancer diagnosis. While concerns have been expressed about proposed population-based BRCA testing for unaffected young women,5 we are heartened by the increasing participation in standard-of-care GCRA by young women with breast cancer. We concur with the authors4 that, unfortunately, it is unlikely that this level of access to, or participation in, GCRA would be found in the community setting or among the economically underserved or ethnic minorities. It is disconcerting that 48% of thosewho did not get testing indicated that they and/or their physician did not think a BRCA mutation was likely, despite the fact that the National Comprehensive Cancer Network (NCCN) guideline2 has recommended genetic counseling and BRCA testing for women with breast cancer diagnosed at 40 years or younger since the outset of the YWS study. The study results did not identify addeddistressasa reasonfordecliningBRCA testingat the time of cancer diagnosis, but the authors2 suggest this as a potential factor, referencingprevious studies that examinedand reported on this finding. The authors2 note the need to explain the practical purpose for genetic testing at the time of a new breast cancer diagnosis and address patient concerns. These issues are most consistently addressed as an essential component of pretest counseling when conducted by clinicians with expertise in GCRA. Comprehensive GCRA also addresses the challengesof conveying complex,uncertainoruninformative test results in a way that reduces confusion and uncertainty about risk management decision-making. Only a few participants (15) indicated concerns about genetic discrimination as a reason they declined BRCA testing. While historically a barrier to genetic testing, additional protectionswith theGenetic Information andNondiscriminationActof2008and lackofevidenceofgeneticdiscrimination6 have reduced these concerns in recent years. There is also a broadening social awareness andacceptability of genetic testing for hereditary predisposition. Thiswasmost dramatically evidencedduring the latterportionof theYWSsampling frame, when in May 2013 actress and director Angelina Jolie announced that she carries a BRCA1 mutation and chose to undergo a bilateral risk reductionmastectomy (RRM) and reconstruction. This announcement generated considerable interest in testing, evidenced by a surge in uptake of GCRA services and testing noted in the YWS study and others in the United States and internationally.7,8 It is notable that most of themedia sound bites on Jolie’s announcement included her clear admonition that although bilateralmastectomywas the answer forher, it is not always the answer—aqualification that is consistent with the NCCN guideline classification of RRM as an option for BRCA carriers.2 The YWS study2 reported a high uptake of RRM (86%) among the women diagnosed as having a BRCA mutation. While the precise timing of genetic testing relative to treatment decision-making was not reported in the study, the authors2 suggest that because testing took place within 3 months of diagnosis formost, andwithin 1 year for all participants, it is likely thatBRCA statuswas available at the time of surgical decision-making in context of breast cancer treatment. This finding is consistent with those of previous studies9-11documentingahighrateofRRMamongwomenwith newlydiagnosedbreast cancer identified asBRCA carriers, including an international study12 that noted significant variaRelated article page 730 Opinion

Risk-reducing medication for primary breast cancer: a network meta-analysis

BACKGROUND Breast cancer is the most frequently occurring malignancy and the second cause of death for cancer in women. Cancer prevention agents (CPAs) are a promising approach to reduce the burden of breast cancer. Currently, two main types of CPAs are available: selective estrogen receptor modulators (SERMs, such as tamoxifen and raloxifene) and aromatase inhibitors (AIs, such as exemestane and anastrozole). OBJECTIVES To assess the efficacy and acceptability of single CPAs for the prevention of primary breast cancer, in unaffected women, at an above-average risk of developing breast cancer.Using a network meta-analysis, to rank single CPAs, based on their efficacy and acceptability (an endpoint that is defined as the inverse of CPA-related toxicity). SEARCH METHODS We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 17 August 2018. We handsearched reference lists to identify additional relevant studies. SELECTION CRITERIA We included randomized controlled trials (RCTs) that enrolled women without a personal history of breast cancer but with an above-average risk of developing a tumor. Women had to be treated with a CPA and followed up to record the occurrence of breast cancer and adverse events. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and conducted risk of bias assessments of the included studies, and assessed the certainty of the evidence using GRADE. Outcome data included incidence of breast carcinoma (both invasive and in situ carcinoma) and adverse events (both overall and severe toxicity). We performed a conventional meta-analysis (for direct comparisons of a single CPA with placebo or a different CPA) and network meta-analysis (for indirect comparisons). MAIN RESULTS We included six studies enrolling 50,927 women randomized to receive one CPA (SERMs: tamoxifen or raloxifene, or AIs: exemestane or anastrozole) or placebo. Three studies compared tamoxifen and placebo, two studies compared AIs (exemestane or anastrozole) versus placebo, and one study compared tamoxifen versus raloxifene. The risk of bias was low for all RCTs.For the tamoxifen versus placebo comparison, tamoxifen likely resulted in a lower risk of developing breast cancer compared to placebo (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.62 to 0.76; 3 studies, 22,832 women; moderate-certainty evidence). In terms of adverse events, tamoxifen likely increased the risk of severe toxicity compared to placebo (RR 1.28, 95% CI 1.12 to 1.47; 2 studies, 20,361 women; moderate-certainty evidence). In particular, women randomized to receive tamoxifen experienced a higher incidence of both endometrial carcinoma (RR 2.26, 95% CI 1.52 to 3.38; high-certainty evidence) and thromboembolism (RR 2.10, 95% CI 1.14 to 3.89; high-certainty evidence) compared to women who received placebo.For the AIs versus placebo comparison, AIs (exemestane or anastrozole) reduced the risk of breast cancer by 53% (RR 0.47, 95% CI 0.35 to 0.63; 2 studies, 8424 women; high-certainty evidence). In terms of adverse events, AIs increased the risk of severe toxicity by 18% (RR 1.18, 95% CI 1.09 to 1.28; 2 studies, 8352 women; high-certainty evidence). These differences were sustained especially by endocrine (e.g. hot flashes), gastrointestinal (e.g. diarrhea), and musculoskeletal (e.g. arthralgia) adverse events, while there were no differences in endometrial cancer or thromboembolism rates between AIs and placebo.For the tamoxifen versus raloxifene comparison, raloxifene probably performed worse than tamoxifen in terms of breast cancer incidence reduction (RR 1.25, 95% CI 1.09 to 1.43; 1 study, 19,490 women; moderate-certainty evidence), but its use was associated with lower toxicity rates (RR 0.87, 95% CI 0.80 to 0.95; 1 study, 19,490 women; moderate-certainty evidence), particularly relating to incidence of endometrial cancer and thromboembolism.An indirect comparison of treatment effects allowed us to compare the SERMs and AIs in this review. In terms of efficacy, AIs (exemestane or anastrozole) may have reduced breast cancer incidence slightly compared to tamoxifen (RR 0.67, 95% CI 0.46 to 0.98; 5 RCTs, 31,256 women); however, the certainty of evidence was low. A lack of model convergence did not allow us to analyze toxicity data. AUTHORS' CONCLUSIONS For women with an above-average risk of developing breast cancer, CPAs can reduce the incidence of this disease. AIs appear to be more effective than SERMs (tamoxifen) in reducing the risk of developing breast cancer. AIs are not associated with an increased risk of endometrial cancer and thromboembolic events. However, long-term data on toxicities from tamoxifen are available while the follow-up toxicity data on unaffected women taking AIs is relatively short. Additional data from direct comparisons are needed to fully address the issues of breast cancer prevention by risk-reducing medications, with special regards to acceptability (i.e. the benefit/harm ratio).

Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab.

PurposeThis study examined the utility of sets of Single Nucleotide Polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC).MethodsWe derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the BCFR and kConFab familial BC cohorts. We compared scores in women based on cancer status at baseline. 2,599 women unaffected at enrollment were followed for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone.ResultsThe mean (SD) PRS baseline was 2.25 (0.35) for the affected and 2.17 (0.35) for unaffected women from combined cohorts (p<10−6). During follow-up, 205 BCs occurred. The hazard ratios for continuous PRS (per SD), and upper vs. lower quintiles were 1.38 (95% CI: 1.22–1.56) and 3.18 (95% CI: 1.84–5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered.ConclusionIncluding BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.